Non-medical use and abuse of prescription opioids is a substantial public health problem in the US. It is not clear what the prevalence is of prescription opioid abuse in patients who are prescribed opioids for chronic pain not related to cancer (i.e., chronic nonmalignant pain, CNMP), but some studies suggest the prevalence is more than minimal. Many CNMP patients are prescribed other CNS-active drugs, in addition to opioids, that serve as adjuvants to either augment pain relief or to treat comorbid psychiatric disorders (e.g., anxiety). Whether these other drugs alter the abuse liability-related effects of opioids has not been studied in humans. Drug interaction studies investigating this notion are warranted because there is evidence in the scientific literature to suggest that some adjuvant drugs when taken in combination with a prescribed opioid might generate greater abuse liability-related effects than the prescription opioid alone. The current application consists of three studies: using an abuse liability assessment methodology we will examine the interactions of oral oxycodone, a drug prescribed for CNMP and that has abuse liability, and two adjuvant drugs from each of three different classes of drugs (muscle relaxants [specific drugs: carisoprodol, metaxalone], benzodiazepines [alprazolam, oxazepam], and anticonvulsants [pregabalin, zonisamide]) in recreational drug users. In each study, one adjuvant will be termed the study drug adjuvant (the drug that we hypothesize will, in combination with oxycodone, produce greater abuse liability-related effects than oxycodone alone), and the other will be termed the comparator negative control adjuvant. Each study will include studying two doses of the study drug adjuvant and one dose of the comparator negative control adjuvant, alone and in combination with oxycodone, using a double-blind, placebo-controlled, crossover design. Key endpoints are abuse liability-related subjective effects (e.g., drug liking). We hypothesize that carisoprodol, alprazolam, and pregabalin, when combined with oxycodone, will produce greater abuse liability-related subjective effects than oxycodone alone. If the hypotheses are supported, we would urge physicians to exercise special caution when prescribing these adjuvants to CNMP patients on long-term opioid therapy, especially those with histories of substance abuse. Other adjuvants, efficacious for a given indication, but devoid of abuse liability-related effects, might be more suitable alternatives. This application consists of a series of clinical laboratory studies to examine a potential modulator of abuse- related effects of prescription opioids that has relevance to the treatment of chronic nonmalignant pain. Our application seeks to determine if different adjuvant drugs that are commonly co-prescribed along with prescription opioids to chronic nonmalignant pain patients produce greater abuse liability-related effects (drug liking) than the prescription opioid alone. The studies have public health ramifications: if an adjuvant drug (e.g., muscle relaxant A) in combination with a prescription opioid produces greater abuse liability-related effects than the opioid alone, such information would be important for clinicians to have in that alternative efficacious adjuvant that do not show such enhancement (e.g., muscle relaxant B) would be the preferred drug to prescribe when treating chronic nonmalignant pain patients. [unreadable] [unreadable] [unreadable]